African American women are disproportionally affected by more aggressive subtypes of breast cancer, such as estrogen receptor (ER)- and triple negative cancers, and are more likely to have worse prognoses than their Caucasian counterparts. Reasons for this racial disparity are unclear. In 2007, shift work that involves disruption of the circadian rhythm, the body's diurnal pattern of timing that operates on about a 24-hour cycle, was classified as a probable carcinogen to humans (group 2A) by the International Agency for Research on Cancer based primarily on findings from breast cancer studies. How the body responds to circadian disruptions is due in part to variations in a set of 30 genes that regulate the circadian rhythm (circadian genes). These circadian genes can influence ER signaling and DNA damage repair, factors that have been linked to a higher risk of breast cancer. Previous studies have also shown that the distribution patterns of variations in the circadian genes differ between African and non-African populations. We hypothesize that variations in the 30 circadian genes are associated with breast cancer risk in African American and Caucasian women. We further hypothesize that the relationship between circadian gene variants and aggressive breast cancer subtypes differ between African Americans and Caucasians, thereby contributing partly to the disparity of incidence rates of the aggressive breast cancer subtypes seen between these two racial groups. We will test these hypotheses by conducting a large study of breast cancer using existing genetic data on African American women from the African American Breast Cancer Consortium (AABC; 3,200 cases, including 1,000 ER-negative cases, and 2,800 controls with data on 7,400 variants in the 30 genes) and Caucasian women from the Breast and Prostate Cancer Cohort Consortium (BPC3; 2,200 ER-negative cases and 2,200 controls with data on 3,800 variants in the 30 genes) for a comprehensive statistical analysis. Using data from the AABC, we will determine whether circadian gene variants are associated with risk of breast cancer [total and ER-negative and ER- /progesterone receptor (PR)-negative subtypes] in African American women (Aim 1); we focus on ER- and ER-/PR-negative subtypes because numbers of triple negative cases are small. Similarly, using data from BPC3, we will determine whether circadian gene variants are associated with risk of ER- and ER-/PR-negative breast cancers in Caucasian women (Aim 2). Results of the race-specific analysis will be used to determine whether the associations between circadian gene variants (2,500 SNPs typed in both AABC and BPC3 women) and ER- or ER-/PR-negative breast cancers differ between African Americans and Caucasians, thereby contributing partly to the racial disparity of these aggressive breast cancer subtypes (Aim 3). Identifying novel risk variants that can clarify reasons for the observed racial disparity of aggressive breast cancer subtypes between African Americans and Caucasians will be particularly useful for providing important information for developing strategies for breast cancer prevention that might minimize the burden of breast cancer in both racial groups.